highlights of prescribing information warnings … · the recommended dose of nucala is 100 mg...

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HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------- WARNINGS AND PRECAUTIONS ----------------------shyThese highlights do not include all the information needed to use NUCALAreg safely and effectively See full prescribing information for NUCALA

NUCALA (mepolizumab) for injection for subcutaneous use Initial US Approval 2015

--------------------------- INDICATIONS AND USAGE---------------------------shyNUCALA is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older and with an eosinophilic phenotype (1) Limitations of Use bull Not for treatment of other eosinophilic conditions (1) bull Not for relief of acute bronchospasm or status asthmaticus (1)

-----------------------DOSAGE AND ADMINISTRATION ----------------------shy100 mg administered subcutaneously once every 4 weeks (2) bull See Full Prescribing Information for instructions on reconstitution of

lyophilized powder and preparation and administration of the injection

--------------------- DOSAGE FORMS AND STRENGTHS---------------------shyFor injection 100 mg of lyophilized powder in a single-dose vial for reconstitution (3)

------------------------------ CONTRAINDICATIONS -----------------------------shyHistory of hypersensitivity to mepolizumab or excipients in the formulation (4)

bull Hypersensitivity reactions (eg angioedema bronchospasm hypotension urticaria rash) have occurred after administration of NUCALA Discontinue NUCALA in the event of a hypersensitivity reaction (51)

bull Do not use to treat acute bronchospasm or status asthmaticus (52) bull Herpes zoster infections have occurred in patients receiving

NUCALA Consider varicella vaccination if medically appropriate prior to starting therapy with NUCALA (53)

bull Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with NUCALA Decrease corticosteroids gradually if appropriate (54)

bull Treat patients with pre-existing helminth infections before therapy with NUCALA If patients become infected while receiving treatment with NUCALA and do not respond to anti-helminth treatment discontinue NUCALA until parasitic infection resolves (55)

------------------------------ ADVERSE REACTIONS -----------------------------shyMost common adverse reactions (incidence greater than or equal to 5) include headache injection site reaction back pain and fatigue (61)

To report SUSPECTED ADVERSE REACTIONS contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or wwwfdagovmedwatch

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised 112015

FULL PRESCRIBING INFORMATION CONTENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

21 Recommended Dosage 22 Preparation and Administration

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

51 Hypersensitivity Reactions 52 Acute Asthma Symptoms or Deteriorating Disease 53 Opportunistic Infections Herpes Zoster 54 Reduction of Corticosteroid Dosage 55 Parasitic (Helminth) Infection

6 ADVERSE REACTIONS 61 Clinical Trials Experience 62 Immunogenicity

7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS

81 Pregnancy

82 Lactation 84 Pediatric Use 85 Geriatric Use

10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY

121 Mechanism of Action 122 Pharmacodynamics 123 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 131 Carcinogenesis Mutagenesis Impairment of Fertility

14 CLINICAL STUDIES 16 HOW SUPPLIEDSTORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

NUCALAreg is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older and with an eosinophilic phenotype [See Clinical Studies (14)] Limitations of Use

bull NUCALA is not indicated for treatment of other eosinophilic conditions

bull NUCALA is not indicated for the relief of acute bronchospasm or status asthmaticus

2 DOSAGE AND ADMINISTRATION

21 Recommended Dosage

NUCALA is for subcutaneous use only 1

Reference ID 3842952

The recommended dose of NUCALA is 100 mg administered once every 4 weeks by subcutaneous injection into the upper arm thigh or abdomen

22 Preparation and Administration NUCALA should be reconstituted and administered by a healthcare professional In line with clinical practice monitoring of patients after administration of biologic agents is recommended [see Warnings and Precautions (51)]

Reconstitution Instructions

1 Reconstitute NUCALA in the vial with 12 mL Sterile Water for Injection USP preferably using a 2- or 3-mL syringe and a 21-G needle The reconstituted solution will contain a concentration of 100 mgmL mepolizumab Do not mix with other medications

2 Direct the stream of Sterile Water for Injection vertically onto the center of the lyophilized cake Gently swirl the vial for 10 seconds with a circular motion at 15-second intervals until the powder is dissolved

Note Do not shake the reconstituted solution during the procedure as this may lead to product foaming or precipitation Reconstitution is typically complete within 5 minutes after the Sterile Water for Injection has been added but it may take additional time

3 If a mechanical reconstitution device (swirler) is used to reconstitute NUCALA swirl at 450 rpm for no longer than 10 minutes Alternatively swirling at 1000 rpm for no longer than 5 minutes is acceptable

4 Visually inspect the reconstituted solution for particulate matter and clarity before use The solution should be clear to opalescent and colorless to pale yellow or pale brown essentially particle free Small air bubbles however are expected and acceptable If particulate matter remains in the solution or if the solution appears cloudy or milky discard the solution

5 If the reconstituted solution is not used immediately

bull store below 30degC (86degF)

bull do not freeze and

bull discard if not used within 8 hours of reconstitution Administration

1 For subcutaneous administration preferably using a 1-mL polypropylene syringe fitted with a disposable 21- to 27-G x 05-inch (13-mm) needle

2 Just before administration remove 1 mL of reconstituted NUCALA Do not shake the reconstituted solution during the procedure as this could lead to product foaming or precipitation

3 Administer the 1-mL injection (equivalent to 100 mg mepolizumab) subcutaneously into the upper arm thigh or abdomen

2


3 DOSAGE FORMS AND STRENGTHS

For injection 100 mg of lyophilized powder in a single-dose vial for reconstitution

4 CONTRAINDICATIONS

NUCALA should not be administered to patients with a history of hypersensitivity to mepolizumab or excipients in the formulation

5 WARNINGS AND PRECAUTIONS

51 Hypersensitivity Reactions

Hypersensitivity reactions (eg angioedema bronchospasm hypotension urticaria rash) have occurred following administration of NUCALA These reactions generally occur within hours of administration but in some instances can have a delayed onset (ie days) In the event of a hypersensitivity reaction NUCALA should be discontinued [see Contraindications (4)]

52 Acute Asthma Symptoms or Deteriorating Disease

NUCALA should not be used to treat acute asthma symptoms or acute exacerbations Do not use NUCALA to treat acute bronchospasm or status asthmaticus Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with NUCALA

53 Opportunistic Infections Herpes Zoster

In controlled clinical trials 2 serious adverse reactions of herpes zoster occurred in subjects treated with NUCALA compared with none in placebo [see Adverse Reactions (61)] Consider varicella vaccination if medically appropriate prior to starting therapy with NUCALA

54 Reduction of Corticosteroid Dosage

Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with NUCALA Reductions in corticosteroid dose if appropriate should be gradual and performed under the direct supervision of a physician Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms andor unmask conditions previously suppressed by systemic corticosteroid therapy

55 Parasitic (Helminth) Infection

Eosinophils may be involved in the immunological response to some helminth infections Patients with known parasitic infections were excluded from participation in clinical trials It is unknown if NUCALA will influence a patientrsquos response against parasitic infections Treat patients with pre-existing helminth infections before initiating therapy with NUCALA If patients become infected while receiving treatment with NUCALA and do not respond to anti-helminth treatment discontinue treatment with NUCALA until infection resolves

3


6 ADVERSE REACTIONS

The following adverse reactions are described in greater detail in other sections

bull Hypersensitivity reactions [see Warnings and Precautions (51)]

bull Opportunistic infections herpes zoster [see Warnings and Precautions (53)]

61 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice

A total of 1327 subjects with asthma were evaluated in 3 randomized placebo-controlled multicenter trials of 24 to 52 weeksrsquo duration (Trials 1 2 and 3) Of these 1192 had a history of 2 or more exacerbations in the year prior to enrollment despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) (Trials 1 and 2) and 135 subjects required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control (Trial 3) All subjects had markers of eosinophilic airway inflammation [see Clinical Studies (14)] Of the subjects enrolled 59 were female 85 were white and subjects ranged in age from 12 to 82 years Mepolizumab was administered subcutaneously or intravenously once every 4 weeks 263 subjects received NUCALA (mepolizumab 100 mg subcutaneous [SC]) for at least 24 weeks Serious adverse events that occurred in more than 1 subject and in a greater percentage of subjects treated with NUCALA (n = 263) than placebo (n = 257) included 1 event herpes zoster (2 subjects vs 0 subjects respectively) Approximately 2 of subjects receiving NUCALA withdrew from clinical trials due to adverse events compared with 3 of subjects receiving placebo

The incidence of adverse reactions in the first 24 weeks of treatment in the 2 confirmatory efficacy and safety trials (Trials 2 and 3) with NUCALA is shown in Table 1

4


Table 1 Adverse Reactions with NUCALA with Greater than or Equal to 3 Incidence and More Common than Placebo in Subjects with Asthma (Trials 2 and 3)

Adverse Reaction

NUCALA (Mepolizumab 100 mg

Subcutaneous) (n = 263)

Placebo (n = 257)

Headache 19 18 Injection site reaction 8 3 Back pain 5 4 Fatigue 5 4 Influenza 3 2 Urinary tract infection 3 2 Abdominal pain upper 3 2 Pruritus 3 2 Eczema 3 lt1 Muscle spasms 3 lt1

52-Week Trial

Adverse reactions from Trial 1 with 52 weeks of treatment with mepolizumab 75 mg intravenous (IV) (n = 153) or placebo (n = 155) and with greater than or equal to 3 incidence and more common than placebo and not shown in Table 1 were abdominal pain allergic rhinitis asthenia bronchitis cystitis dizziness dyspnea ear infection gastroenteritis lower respiratory tract infection musculoskeletal pain nasal congestion nasopharyngitis nausea pharyngitis pyrexia rash toothache viral infection viral respiratory tract infection and vomiting In addition 3 cases of herpes zoster occurred in subjects treated with mepolizumab 75 mg IV compared with 2 subjects in the placebo group

Systemic Reactions including Hypersensitivity Reactions

In Trials 1 2 and 3 described above the percentage of subjects who experienced systemic (allergic and non-allergic) reactions was 7 in the placebo group and 10 in the group receiving NUCALA Systemic allergichypersensitivity reactions were reported by 2 of subjects in the placebo group and 1 of subjects in the group receiving NUCALA The most commonly reported manifestations of systemic allergichypersensitivity reactions reported in the group receiving NUCALA included rash pruritus headache and myalgia Systemic non-allergic reactions were reported by 2 of subjects in the group receiving NUCALA and 3 of subjects in the placebo group The most commonly reported manifestations of systemic non-allergic reactions reported in the group receiving NUCALA included rash flushing and myalgia A

5


majority of the systemic reactions in subjects receiving NUCALA (57) were experienced on the day of dosing

Injection Site Reactions

Injection site reactions (eg pain erythema swelling itching burning sensation) occurred at a rate of 8 in subjects treated with NUCALA compared with 3 in subjects treated with placebo

Long-Term Safety

Nine hundred ninety-eight (998) subjects have received NUCALA in ongoing open-label extension studies during which additional cases of herpes zoster have been reported The overall adverse event profile was similar to the asthma trials described above

62 Immunogenicity

Overall 15260 (6) of subjects treated with NUCALA developed anti-mepolizumab antibodies The reported frequency may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentration Neutralizing antibodies were detected in 1 subject receiving mepolizumab Anti-mepolizumab antibodies slightly increased (approximately 20) the clearance of mepolizumab There was no evidence of a correlation between anti-mepolizumab antibody titers and change in eosinophil level The clinical relevance of the presence of anti-mepolizumab antibodies is not known

The data reflect the percentage of patients whose test results were positive for antibodies to mepolizumab in specific assays The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity assay methodology sample handling timing of sample collection concomitant medications and underlying disease

7 DRUG INTERACTIONS

Formal drug interaction trials have not been performed with NUCALA

8 USE IN SPECIFIC POPULATIONS

81 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NUCALA during pregnancy Healthcare providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting wwwmothertobabyorgasthma

Risk Summary

The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk Monoclonal antibodies such as mepolizumab are transported across the placenta in a linear fashion as pregnancy progresses therefore potential effects on a fetus are

6


likely to be greater during the second and third trimester of pregnancy In a prenatal and postnatal development study conducted in cynomolgus monkeys there was no evidence of fetal harm with IV administration of mepolizumab throughout pregnancy at doses that produced exposures up to approximately 30 times the exposure at the maximum recommended human dose (MRHD) of 100 mg SC [see Data]

In the US general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 and 15 to 20 respectively

Clinical Considerations

Disease-Associated Maternal andor Embryo-Fetal Risk In women with poorly or moderately controlled asthma evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity low birth weight and small for gestational age in the neonate The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control

Data

Animal Data In a prenatal and postnatal development study pregnant cynomolgus monkeys received mepolizumab from gestation days 20 to 140 at doses that produced exposures up to approximately 30 times that achieved with the MRHD (on an AUC basis with maternal IV doses up to 100 mgkg once every 4 weeks) Mepolizumab did not elicit adverse effects on fetal or neonatal growth (including immune function) up to 9 months after birth Examinations for internal or skeletal malformations were not performed Mepolizumab crossed the placenta in cynomolgus monkeys Concentrations of mepolizumab were approximately 24 times higher in infants than in mothers up to day 178 postpartum Levels of mepolizumab in milk were less than or equal to 05 of maternal serum concentration

In a fertility early embryonic and embryo-fetal development study pregnant CD-1 mice received an analogous antibody which inhibits the activity of murine IL-5 at an IV dose of 50 mgkg once per week throughout gestation The analogous antibody was not teratogenic in mice Embryo-fetal development of IL-5ndashdeficient mice has been reported to be generally unaffected relative to wild-type mice

82 Lactation

Risk Summary

There is no information regarding the presence of mepolizumab in human milk the effects on the breastfed infant or the effects on milk production However mepolizumab is a humanized monoclonal antibody (IgG1 kappa) and immunoglobulin G (IgG) is present in human milk in small amounts Mepolizumab was present in the milk of cynomolgus monkeys postpartum following dosing during pregnancy [see Use in Specific Populations (81)] The developmental and health benefits of breastfeeding should be considered along with the motherrsquos clinical need

7


for NUCALA and any potential adverse effects on the breastfed infant from mepolizumab or from the underlying maternal condition

84 Pediatric Use

The safety and efficacy in pediatric patients younger than 12 years have not been established A total of 28 adolescents aged 12 to 17 years with asthma were enrolled in the phase 3 studies Of these 25 were enrolled in the 32-week exacerbation trial (Trial 2) and had a mean age of 148 years Subjects had a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids and had blood eosinophils of greater than or equal to 150 cellsmcL at screening or greater than or equal to 300 cellsmcL within 12 months prior to enrollment [See Clinical Studies (14)] Subjects had a reduction in the rate of exacerbations that trended in favor of mepolizumab Of the 19 adolescents who received mepolizumab 9 received NUCALA and the mean apparent clearance in these subjects was 35 less than that of adults The adverse event profile in adolescents was generally similar to the overall population in the phase 3 studies [see Adverse Reactions (61)]

85 Geriatric Use

Clinical trials of NUCALA did not include sufficient numbers of subjects aged 65 years and older that received NUCALA (n = 38) to determine whether they respond differently from younger subjects Other reported clinical experience has not identified differences in responses between the elderly and younger patients In general dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic renal or cardiac function and of concomitant disease or other drug therapy Based on available data no adjustment of the dosage of NUCALA in geriatric patients is necessary but greater sensitivity in some older individuals cannot be ruled out

10 OVERDOSAGE

Single doses of up to 1500 mg have been administered intravenously to subjects in a clinical trial with eosinophilic disease without evidence of dose-related toxicities

There is no specific treatment for an overdose with mepolizumab If overdose occurs the patient should be treated supportively with appropriate monitoring as necessary

11 DESCRIPTION

Mepolizumab is a humanized IL-5 antagonist monoclonal antibody Mepolizumab is produced by recombinant DNA technology in Chinese hamster ovary cells Mepolizumab has a molecular weight of approximately 149 kDa

NUCALA is supplied as a sterile white to off-white preservative-free lyophilized powder for subcutaneous injection after reconstitution Upon reconstitution with 12 mL of Sterile Water for Injection USP [see Dosage and Administration (21)] the resulting concentration is 100 mgmL

8


and delivers 1 mL Each single-dose vial delivers mepolizumab 100 mg polysorbate 80 (067 mg) sodium phosphate dibasic heptahydrate (714 mg) and sucrose (160 mg) with a pH of 70

12 CLINICAL PHARMACOLOGY

121 Mechanism of Action

Mepolizumab is an interleukin-5 antagonist (IgG1 kappa) IL-5 is the major cytokine responsible for the growth and differentiation recruitment activation and survival of eosinophils Mepolizumab binds to IL-5 with a dissociation constant of 100 pM inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface Inflammation is an important component in the pathogenesis of asthma Multiple cell types (eg mast cells eosinophils neutrophils macrophages lymphocytes) and mediators (eg histamine eicosanoids leukotrienes cytokines) are involved in inflammation Mepolizumab by inhibiting IL-5 signaling reduces the production and survival of eosinophils however the mechanism of mepolizumab action in asthma has not been definitively established

122 Pharmacodynamics

The pharmacodynamic response (blood eosinophil reduction) following repeat doses of mepolizumab administered subcutaneously or intravenously was evaluated in subjects with asthma and blood eosinophil levels greater than 200 cellsmcL Subjects received 1 of 4 mepolizumab treatments (administered every 28 days for a total of 3 doses) 125 mg SC 125 mg SC 250 mg SC or 75 mg IV Sixty-six (66) of the 70 randomized subjects completed the trial Compared with baseline levels blood eosinophils decreased in a dose-dependent manner A reduction in blood eosinophil levels was observed in all treatment groups by Day 3 On Day 84 (4 weeks post-last dose) the observed geometric mean reduction from baseline in blood eosinophils was 64 78 84 and 90 in the 125-mg SC 75-mg IV 125-mg SC and 250-mg SC treatment groups respectively The model-predicted SC doses providing 50 and 90 of maximal reduction of blood eosinophils at Day 84 were estimated to be 11 and 99 mg respectively These results along with the clinical efficacy data from the dose-ranging exacerbation trial (Trial 1) supported the evaluation of mepolizumab 75 mg IV and 100 mg SC in the confirmatory trials [see Clinical Studies (14)] Following SC administration of mepolizumab 100 mg every 4 weeks for 32 weeks (Trial 2) blood eosinophils were reduced to a geometric mean count of 40 cellsmcL which corresponds to a geometric mean reduction of 84 compared with placebo This magnitude of reduction was observed within 4 weeks of treatment and was maintained throughout the treatment period

123 Pharmacokinetics

Following SC dosing in subjects with asthma mepolizumab exhibited approximately dose-proportional pharmacokinetics over a dose range of 125 to 250 mg

9


Absorption

Following 100-mg SC administration in the upper arm of subjects with asthma the bioavailability of mepolizumab was estimated to be approximately 80

Following repeat SC administration once every 4 weeks there was approximately a 2-fold accumulation at steady state

Distribution

The population central volume of distribution of mepolizumab in patients with asthma is estimated to be 36 L for a 70-kg individual

Metabolism

Mepolizumab is a humanized IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue

Elimination

Following SC administration of mepolizumab the mean terminal half-life (t12) ranged from 16 to 22 days The population apparent systemic clearance of mepolizumab in patients with asthma is estimated to be 028 Lday for a 70-kg individual

Specific Populations

Race and Gender A population pharmacokinetics analysis indicated there was no significant effect of race and gender on mepolizumab clearance

Age A population pharmacokinetics analysis of subjects ranging in age from 12 to 82 years indicated there was no significant effect of age on mepolizumab clearance

Renal Impairment No clinical trials have been conducted to investigate the effect of renal impairment on the pharmacokinetics of mepolizumab Based on population pharmacokinetic analyses mepolizumab clearance was comparable between subjects with creatinine clearance values between 50 and 80 mLmin and patients with normal renal function There are limited data available in subjects with creatinine clearance values less than 50 mLmin however mepolizumab is not cleared renally

Hepatic Impairment No clinical trials have been conducted to investigate the effect of hepatic impairment on the pharmacokinetics of mepolizumab Since mepolizumab is degraded by widely distributed proteolytic enzymes not restricted to hepatic tissue changes in hepatic function are unlikely to have any effect on the elimination of mepolizumab

Drug-Drug Interactions No formal drug interaction studies have been conducted with NUCALA In the population pharmacokinetics analyses of the phase 3 studies there was no evidence of an effect of commonly coadministered small molecule drugs on mepolizumab exposure

10


13 NONCLINICAL TOXICOLOGY

131 Carcinogenesis Mutagenesis Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of mepolizumab Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection However other reports indicate that eosinophil infiltration into tumors can promote tumor growth Therefore the malignancy risk in humans from an antibody to IL-5 such as mepolizumab is unknown

Male and female fertility were unaffected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys treated with mepolizumab for 6 months at IV doses up to 100 mgkg once every 4 weeks (approximately 70 times the MRHD on an AUC basis) Mating and reproductive performance were unaffected in male and female CD-1 mice treated with an analogous antibody which inhibits the activity of murine IL-5 at an IV dose of 50 mgkg once per week

14 CLINICAL STUDIES

The asthma development program for NUCALA included 3 double-blind randomized placebo-controlled trials 1 dose-ranging and exacerbation trial (Trial 1) and 2 confirmatory trials (Trials 2 and 3) Mepolizumab was administered every 4 weeks in all 3 trials as add-on to background treatment All subjects continued their background asthma therapy throughout the duration of the trials

Dose-Ranging and Exacerbation Trial

Trial 1 was a 52-week dose-ranging and exacerbation-reduction trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids Subjects enrolled in this trial were required to have at least 1 of the following 4 pre-specified criteria in the previous 12 months blood eosinophil count greater than or equal to 300 cellsmcL sputum eosinophil count greater than or equal to 3 exhaled nitric oxide concentration greater than or equal to 50 ppb or deterioration of asthma control after less than or equal to 25 reduction in regular maintenance inhaled corticosteroidsoral corticosteroids Three IV doses of mepolizumab (75 250 and 750 mg) administered once every 4 weeks were evaluated compared with placebo Results from this trial and the pharmacodynamic study supported the evaluation of mepolizumab 75 mg IV and 100 mg SC in the subsequent trials [see Clinical Pharmacology (122)] NUCALA is not indicated for IV use and should only be administered by the SC route

Confirmatory Trials

A total of 711 subjects with asthma were studied in the 2 confirmatory trials (Trials 2 and 3) In these 2 trials subjects were required to have blood eosinophils of greater than or equal to

11


150 cellsmcL at screening (within 6 weeks of dosing) or blood eosinophils of greater than or equal to 300 cellsmcL within 12 months of enrollment The screening blood eosinophils of greater than or equal to 150 cellsmcL criterion was derived from exploratory analyses of data from Trial 1 Trial 2 was a 32-week placebo- and active-controlled trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids Subjects received mepolizumab 75 mg IV (n = 191) NUCALA (n = 194) or placebo (n = 191) once every 4 weeks for 32 weeks

Trial 3 was a 24-week oral corticosteroid-reduction trial in subjects with asthma who required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control Subjects in Trial 3 were not required to have a history of exacerbations in the prior year Subjects received NUCALA (n = 69) or placebo (n = 66) once every 4 weeks for 24 weeks The baseline mean oral corticosteroid use was similar in the 2 treatment groups 132 mg in the placebo group and 124 mg in the group receiving NUCALA

The demographics and baseline characteristics of these 3 trials are provided in Table 2

Table 2 Demographics and Baseline Characteristics of Asthma Trials Trial 1

(N = 616) Trial 2

(N = 576) Trial 3

(N = 135) Mean age (yr) 49 50 50 Female n () 387 (63) 328 (57) 74 (55) White n () 554 (90) 450 (78) 128 (95) Duration of asthma mean (yr) 19 20 19 Never smoked n () 483 (78) 417 (72) 82 (61) Baseline FEV1 L 188 182 195 Baseline predicted FEV1 60 61 59 Baseline reversibility 25 27 26 Baseline post-SABA FEV1FVC 067 066 066 Geometric mean eosinophil count at baseline cellsmcL

250 290 240

Mean number of exacerbations in previous year

36 36 31

FEV1 = Forced expiratory volume in 1 second SABA = Short-acting beta2-agonist FVC = Forced vital capacity

12


Exacerbations

The primary endpoint for Trials 1 and 2 was the frequency of exacerbations defined as worsening of asthma requiring use of oralsystemic corticosteroids andor hospitalization andor emergency department visits For subjects on maintenance oral corticosteroids an exacerbation requiring oral corticosteroids was defined as the use of oralsystemic corticosteroids at least double the existing dose for at least 3 days Compared with placebo subjects receiving NUCALA or mepolizumab 75 mg IV experienced significantly fewer exacerbations Additionally compared with placebo there were fewer exacerbations requiring hospitalization andor emergency department visits and exacerbations requiring only in-patient hospitalization with NUCALA (Table 3)

13


Table 3 Rate of Exacerbations in Trials 1 and 2 (Intent-to-Treat Population)

Trial Treatment

Exacerbations per Year

Rate Difference Rate Ratio (95 CI)

All Exacerbations Trial 1 Placebo (n = 155) 240

Mepolizumab 75 mg IV (n = 153) 124 116 052 (039 069)

Trial 2 Placebo (n = 191) 174 Mepolizumab 75 mg IV (n = 191) 093 081 053

(040 072) NUCALA 100 mg SC (n = 194) 083 091 047

(035 064) Exacerbations requiring hospitalizationemergency room visit Trial 1 Placebo (n = 155) 043



(033 141) NUCALA 100 mg SC (n = 194) 008 012 039

(018 083) Exacerbations requiring hospitalization Trial 1 Placebo (n = 155) 018



(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)

The time to first exacerbation was longer for the groups receiving NUCALA and mepolizumab 75 mg IV compared with placebo in Trial 2 (Figure 1)

14


Figure 1 Kaplan-Meier Cumulative Incidence Curve for Time to First Exacerbation (Trial 2)

Trial 1 data were explored to determine criteria that could identify subjects likely to benefit from treatment with NUCALA The exploratory analysis suggested that baseline blood eosinophil count of 150 cellsmcL or greater was a potential predictor of treatment benefit Exploratory analysis of Trial 2 data also suggested that baseline blood eosinophil count (obtained within 6 weeks of initiation of dosing) of 150 cellsmcL or greater was a potential predictor of efficacy and showed a trend of greater exacerbation benefit with increasing blood eosinophil count In Trial 2 subjects enrolled solely on the basis of the historical blood eosinophil count of 300 cellsmcL or greater in the past 12 months but who had a baseline blood eosinophil count less than 150 cellsmcL had virtually no exacerbation benefit following treatment with NUCALA compared with placebo

The Asthma Control Questionnaire-5 (ACQ-5) was assessed in Trials 1 and 2 and the St Georges Respiratory Questionnaire (SGRQ) was assessed in Trial 2 In Trial 1 the ACQ-5 responder rate (defined as a change in score of 05 or more as threshold) for the 75-mg IV mepolizumab arm was 47 compared with 50 for placebo with odds ratio of 11 (95 CI 07 17) In Trial 2 the ACQ-5 responder rate for the treatment arm for NUCALA was 57 compared with 45 for placebo with odds ratio of 18 (95 CI 12 28) In Trial 2 the SGRQ responder rate (defined as a change in score of 4 or more as threshold) for the treatment arm for NUCALA was 71 compared with 55 for placebo with odds ratio of 21 (95 CI 13 32)

Oral Corticosteroid Reduction

Trial 3 evaluated the effect of NUCALA on reducing the use of maintenance oral corticosteroids The primary endpoint was the percent reduction of oral corticosteroid dose during Weeks 20 to 24 compared with baseline dose while maintaining asthma control Subjects were classified according to their change in oral corticosteroid use during the trial with the following categories

15


90 to 100 decrease 75 to lt90 decrease 50 to lt75 decrease gt0 to lt50 decrease and no improvement (ie no change or any increase or lack of asthma control or withdrawal of treatment) Compared with placebo subjects receiving NUCALA achieved greater reductions in daily maintenance oral corticosteroid dose while maintaining asthma control Sixteen (23) subjects in the group receiving NUCALA versus 7 (11) in the placebo group had a 90 to 100 reduction in their oral corticosteroid dose Twenty-five (36) subjects in the group receiving NUCALA versus 37 (56) in the placebo group were classified as having no improvement for oral corticosteroid dose Additionally 54 of subjects treated with NUCALA achieved at least a 50 reduction in the daily prednisone dose compared with 33 of subjects treated with placebo (95 CI for difference 4 37) An exploratory analysis was also performed on the subgroup of 29 subjects in Trial 3 who had an average baseline and screening blood eosinophil count less than 150 cellsmcL Five (29) subjects in the group receiving NUCALA versus 0 (0) in the placebo group had a 90 to 100 reduction in their dose Four (24) subjects in the group receiving NUCALA versus eight (67) in the placebo group were classified as having no improvement for oral corticosteroid dose The ACQ and SGRQ were also assessed in Trial 3 and showed results similar to those in Trial 2

Lung Function

Change from baseline in mean forced expiratory volume in 1 second (FEV1) was measured in all 3 trials and is presented in Table 4 Compared with placebo NUCALA did not provide consistent improvements in mean change from baseline in FEV1

Table 4 Change from Baseline in FEV1 (mL)

Trial Difference from Placebo in Mean Change from Baseline FEV1 mL (95 CI)

Week 12 Week 24 Weeks 3252 1a

2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d

NA a Dose = 75 mg IV b FEV1 at Week 52 c Dose = 100 mg SC d FEV1 at Week 32

The effect of mepolizumab on lung function was also studied in a 12-week placebo-controlled trial enrolling patients with asthma on a moderate dose of inhaled corticosteroid with evidence of symptoms and lung function impairment Enrollment was not dependent on a history of exacerbations or a pre-specified eosinophil count Change from baseline in FEV1 at Week 12 was numerically lower in the mepolizumab treatment groups than the placebo group

16


16 HOW SUPPLIEDSTORAGE AND HANDLING

NUCALA is supplied as a sterile preservative-free lyophilized powder for reconstitution and subcutaneous injection in cartons of 1 single-dose glass vial and a flip-off seal The vial stopper is not made with natural rubber latex NUCALA is available as

100-mg single-dose vial (NDC 0173-0881-01)

Store below 25degC (77degF) Do not freeze Store in the original package to protect from light

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information)

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions (eg angioedema bronchospasm hypotension urticaria rash) have occurred after administration of NUCALA Instruct patients to contact their physicians if such reactions occur

Not for Acute Symptoms or Deteriorating Disease

Inform patients that NUCALA does not treat acute asthma symptoms or acute exacerbations Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with NUCALA

Opportunistic Infections Herpes Zoster

Inform patients that herpes zoster infections have occurred in patients receiving NUCALA and where medically appropriate inform patients varicella vaccination should be considered before starting treatment with NUCALA

Reduction of Corticosteroid Dosage

Inform patients to not discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms andor unmask conditions previously suppressed by systemic corticosteroid therapy


Inform women there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NUCALA during pregnancy and that they can enroll in the Pregnancy Exposure Registry by calling 1-877-311-8972 or by visiting wwwmothertobabyorgasthma [see Use in Specific Populations (81)]

NUCALA is a registered trademark of the GSK group of companies

17


Manufactured by GlaxoSmithKline LLC Philadelphia PA 19112 US License Number 1727

Distributed by

GlaxoSmithKline Research Triangle Park NC 27709

copy2015 the GSK group of companies All rights reserved

NCLxPI

PHARMACISTmdashDETACH HERE AND GIVE PATIENT INFORMATION TO PATIENT

Patient Information NUCALAreg [new-kaprime la]

(mepolizumab) for injection for subcutaneous use

What is NUCALA

NUCALA is a prescription medicine used with other asthma medicines for the maintenance treatment of asthma in people aged 12 years and older whose asthma is not controlled with their current asthma medicines NUCALA helps prevent severe asthma attacks (exacerbations) Medicines such as NUCALA reduce blood eosinophils Eosinophils are a type of white blood cells that may contribute to your asthma bull NUCALA is not used to treat other problems caused by eosinophils bull NUCALA is not used to treat sudden breathing problems

It is not known if NUCALA is safe and effective in children under 12 years of age

Do not use NUCULA if you are allergic to mepolizumab or any of the ingredients in NUCALA See the end of this leaflet for a complete list of ingredients in NUCALA

18


Before receiving NUCALA tell your healthcare provider about all of your medical conditions including if you bull have a parasitic (helminth) infection bull have not had chickenpox (varicella) or the chickenpox vaccine bull are taking oral or inhaled corticosteroid medicines Do not stop taking your corticosteroid medicines

unless instructed by your healthcare provider This may cause other symptoms that were controlled by the corticosteroid medicine to come back

bull are pregnant or plan to become pregnant It is not known if NUCALA may harm your unborn baby bull Pregnancy Registry There is a pregnancy registry for women who receive NUCALA while

pregnant The purpose of the registry is to collect information about the health of you and your baby You can talk to your healthcare provider about how to take part in this registry or you can get more information and register by calling 1-877-311-8972 or go to wwwmothertobabyorgasthma

bull are breastfeeding or plan to breastfeed You and your healthcare provider should decide if you will use NUCALA and breastfeed You should not do both without talking with your healthcare provider first

bull Tell your healthcare provider about all the medicines you take including prescription and over-theshycounter medicines vitamins and herbal supplements

bull Do not stop taking your other asthma medicines unless instructed to do so by your healthcare provider

How will I receive NUCALA

A healthcare provider will inject NUCALA under your skin (subcutaneously) 1 time every 4 weeks

What are the possible side effects of NUCALA

NUCALA can cause serious side effects including bull allergic (hypersensitivity) reactions Serious allergic reactions can happen after you get your

NUCALA injection Allergic reactions can sometimes happen hours or days after you get a dose of NUCALA Tell your healthcare provider or get emergency help right away if you have any of the following symptoms of an allergic reaction bull swelling of your face mouth and tongue bull breathing problems bull fainting dizziness feeling lightheaded (low blood pressure) bull rash bull hives

bull Herpes zoster infections that can cause shingles have happened in people who received NUCALA

The most common side effects of NUCALA include headache injection site reactions (pain redness swelling itching or a burning feeling at the injection site) back pain and weakness (fatigue)

These are not all the possible side effects of NUCALA

Call your doctor for medical advice about side effects You may report side effects to FDA at 1-800-FDAshy1088

19


General information about the safe and effective use of NUCALA

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet You can ask your pharmacist or healthcare provider for information about NUCALA that is written for health professionals

What are the ingredients in NUCALA

Active Ingredient mepolizumab Inactive Ingredients polysorbate 80 sodium phosphate dibasic heptahydrate and sucrose

For more information call GlaxoSmithKline (GSK) at 1-888-825-5249 or visit wwwNUCALAcom NUCALA is a trademark of the GSK group of companies

Manufactured by GlaxoSmithKline LLC Philadelphia PA 19112 US License No 1727

Distributed by



NCLxPIL

This Patient Information has been approved by the US Food and Drug Administration Approved November 2015

20


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(b) (4)

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(b) (4)

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(b) (4)


(b) (4)

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(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


The recommended dose of NUCALA is 100 mg administered once every 4 weeks by subcutaneous injection into the upper arm thigh or abdomen

22 Preparation and Administration NUCALA should be reconstituted and administered by a healthcare professional In line with clinical practice monitoring of patients after administration of biologic agents is recommended [see Warnings and Precautions (51)]

Reconstitution Instructions

1 Reconstitute NUCALA in the vial with 12 mL Sterile Water for Injection USP preferably using a 2- or 3-mL syringe and a 21-G needle The reconstituted solution will contain a concentration of 100 mgmL mepolizumab Do not mix with other medications

2 Direct the stream of Sterile Water for Injection vertically onto the center of the lyophilized cake Gently swirl the vial for 10 seconds with a circular motion at 15-second intervals until the powder is dissolved

Note Do not shake the reconstituted solution during the procedure as this may lead to product foaming or precipitation Reconstitution is typically complete within 5 minutes after the Sterile Water for Injection has been added but it may take additional time

3 If a mechanical reconstitution device (swirler) is used to reconstitute NUCALA swirl at 450 rpm for no longer than 10 minutes Alternatively swirling at 1000 rpm for no longer than 5 minutes is acceptable

4 Visually inspect the reconstituted solution for particulate matter and clarity before use The solution should be clear to opalescent and colorless to pale yellow or pale brown essentially particle free Small air bubbles however are expected and acceptable If particulate matter remains in the solution or if the solution appears cloudy or milky discard the solution

5 If the reconstituted solution is not used immediately

bull store below 30degC (86degF)

bull do not freeze and

bull discard if not used within 8 hours of reconstitution Administration

1 For subcutaneous administration preferably using a 1-mL polypropylene syringe fitted with a disposable 21- to 27-G x 05-inch (13-mm) needle

2 Just before administration remove 1 mL of reconstituted NUCALA Do not shake the reconstituted solution during the procedure as this could lead to product foaming or precipitation

3 Administer the 1-mL injection (equivalent to 100 mg mepolizumab) subcutaneously into the upper arm thigh or abdomen

2




4 CONTRAINDICATIONS













3


6 ADVERSE REACTIONS








4



Adverse Reaction



Placebo (n = 257)


52-Week Trial




5





Long-Term Safety


62 Immunogenicity



7 DRUG INTERACTIONS



81 Pregnancy



Risk Summary


6






Data



82 Lactation

Risk Summary


7



84 Pediatric Use


85 Geriatric Use


10 OVERDOSAGE



11 DESCRIPTION



8










9


Absorption



Distribution


Metabolism


Elimination








10






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)




4 CONTRAINDICATIONS













3


6 ADVERSE REACTIONS








4



Adverse Reaction



Placebo (n = 257)


52-Week Trial




5





Long-Term Safety


62 Immunogenicity



7 DRUG INTERACTIONS



81 Pregnancy



Risk Summary


6






Data



82 Lactation

Risk Summary


7



84 Pediatric Use


85 Geriatric Use


10 OVERDOSAGE



11 DESCRIPTION



8










9


Absorption



Distribution


Metabolism


Elimination








10






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


6 ADVERSE REACTIONS








4



Adverse Reaction



Placebo (n = 257)


52-Week Trial




5





Long-Term Safety


62 Immunogenicity



7 DRUG INTERACTIONS



81 Pregnancy



Risk Summary


6






Data



82 Lactation

Risk Summary


7



84 Pediatric Use


85 Geriatric Use


10 OVERDOSAGE



11 DESCRIPTION



8










9


Absorption



Distribution


Metabolism


Elimination








10






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)



Adverse Reaction



Placebo (n = 257)


52-Week Trial




5





Long-Term Safety


62 Immunogenicity



7 DRUG INTERACTIONS



81 Pregnancy



Risk Summary


6






Data



82 Lactation

Risk Summary


7



84 Pediatric Use


85 Geriatric Use


10 OVERDOSAGE



11 DESCRIPTION



8










9


Absorption



Distribution


Metabolism


Elimination








10






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)





Long-Term Safety


62 Immunogenicity



7 DRUG INTERACTIONS



81 Pregnancy



Risk Summary


6






Data



82 Lactation

Risk Summary


7



84 Pediatric Use


85 Geriatric Use


10 OVERDOSAGE



11 DESCRIPTION



8










9


Absorption



Distribution


Metabolism


Elimination








10






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)






Data



82 Lactation

Risk Summary


7



84 Pediatric Use


85 Geriatric Use


10 OVERDOSAGE



11 DESCRIPTION



8










9


Absorption



Distribution


Metabolism


Elimination








10






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)



84 Pediatric Use


85 Geriatric Use


10 OVERDOSAGE



11 DESCRIPTION



8










9


Absorption



Distribution


Metabolism


Elimination








10






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)










9


Absorption



Distribution


Metabolism


Elimination








10






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


Absorption



Distribution


Metabolism


Elimination








10






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)






14 CLINICAL STUDIES




Confirmatory Trials


11






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)






(N = 616) Trial 2

(N = 576) Trial 3


250 290 240


36 36 31


12


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


Exacerbations


13



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)



Trial Treatment






(040 072) NUCALA 100 mg SC (n = 194) 083 091 047




(033 141) NUCALA 100 mg SC (n = 194) 008 012 039




(023 166) NUCALA 100 mg SC (n = 194) 003 007 031

(011 091)


14







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)







15



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)



Lung Function





2c

3c

10 (-87 108) 52 (-30 134) 56 (-91 203)

5 (-98 108) 76 (-6 159)

114 (-42 271)

61 (-39 161)b

98 (11 184)d



16



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)



















17



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)



Distributed by



NCLxPI




What is NUCALA




18


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


















19








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)








Distributed by



NCLxPIL


20


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4)

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


(b) (4

(b) (4)

(b) (4)


highlights of prescribing information warnings … · the recommended dose of nucala is 100 mg...

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